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PMID:17003038

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Citation

Hatanaka, T, Hatanaka, Y and Setou, M (2006) Regulation of amino acid transporter ATA2 by ubiquitin ligase Nedd4-2. J. Biol. Chem. 281:35922-30

Abstract

We report here that ubiquitin ligase Nedd4-2 regulates amino acid transporter ATA2 activity on the cell surface. We first found that a proteasome inhibitor MG132 increased the uptake of alpha-(methylamino)isobutyric acid, a model substrate for amino acid transport system A, in 3T3-L1 adipocytes as well as the preadipocytes. Transient expression of Nedd4-2 in Xenopus oocytes and Chinese hamster ovary cells down-regulated the ATA2 transport activity induced by injected cRNA and transfected cDNA, respectively. Neither the Nedd4-2 mutant with defective catalytic domain nor c-Cbl affected the ATA2 activity significantly. RNA-mediated interference of Nedd4-2 increased the ATA2 activity in the cells, and this was associated with decreased polyubiquitination of ATA2 on the cell surface membrane. Immunofluorescent analysis of Nedd4-2 in the adipocytes stably transfected with the enhanced green fluorescent protein (EGFP)-tagged ATA2 showed the co-localization of Nedd4-2 and EGFP-ATA2 in the plasma membrane but not in the perinuclear ATA2 storage site, supporting the idea that the primary site for the ubiquitination of ATA2 is the plasma membrane. These data suggest that ATA2 on the plasma membrane is subject to polyubiquitination by Nedd4-2 with consequent endocytotic sequestration and proteasomal degradation and that this process is an important determinant of the density of ATA2 functioning on the cell surface.

Links

PubMed Online version:10.1074/jbc.M606577200

Keywords

3T3-L1 Cells; Amino Acid Transport System A/biosynthesis; Amino Acid Transport System A/chemistry; Aminoisobutyric Acids/pharmacology; Animals; CHO Cells; Cricetinae; Endosomal Sorting Complexes Required for Transport; Gene Expression Regulation; Green Fluorescent Proteins/pharmacology; Leupeptins/pharmacology; Mice; Oocytes/metabolism; Protease Inhibitors/pharmacology; Ubiquitin/chemistry; Ubiquitin/metabolism; Ubiquitin-Protein Ligases/biosynthesis; Ubiquitin-Protein Ligases/chemistry; Ubiquitin-Protein Ligases/physiology; Xenopus

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GLUT4

located_in

GO:0030140: trans-Golgi network transport vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLUT4

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:EEA1

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:S38A2

acts_upstream_of_or_within

GO:0006865: amino acid transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:S38A2

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:S38A2

enables

GO:0015171: amino acid transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:GOGA2

located_in

GO:0005794: Golgi apparatus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:STX6

located_in

GO:0005802: trans-Golgi network

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:EEA1

part_of

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GOGA2

part_of

GO:0005794: Golgi apparatus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

See also

References

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